Metrology and Nonlinear Acoustics Bioeffects of High Intensity Focused Ultrasound

描述(申请人提供)：高强度聚焦超声(HIFU)是一种新兴的医学技术，可以在不损害中间组织的情况下，对毫米大小的焦点“热点”内的目标组织进行热消融。在最近的HIFU研究中，人们对使用纯机械破坏组织而不进行热凝(组织摩擦)也很感兴趣。尽管HIFU成功地用于治疗一些良性肿瘤和恶性肿瘤，但由于安全性和有效性的监管标准不完善，这项技术在临床上的广泛接受度受到了阻碍。目前的限制包括：(A)缺乏确定HIFU场特征的计量标准；(B)对高声强下的热和机械生物效应的机械理解不完整，这阻碍了在提供暴露测量信息的情况下量化剂量；(C)临床挑战，如治疗时间长，肋骨等声学障碍，以及成本效益高的成像指导有限。这项建议解决了这些限制，特别关注在高功率水平下的治疗。在拨款的最初几年，我们探索了利用非线性声学和 开发了用于表征强烈声场的计量工具。我们发现，冲击波的形成导致的超声波吸收是相同强度的谐波的10-100倍；因此，100℃的沸腾条件可以在毫秒内达到。我们开发了一种治疗方法，使用毫秒长的高压脉冲序列在焦点处发出冲击波。在这样的治疗方案中，组织消融速度加快，沸腾的启动便于超声成像引导，组织损伤可以被控制为表现为机械损伤、热损伤或两者兼而有之。这项建议的具体目标是建立在先前工作的基础上，以推动非线性HIFU方法走向临床应用。在目标1中，我们将把HIFU换能器的特性扩展到复杂的阵列源，并将定义适合于临床HIFU系统性能评估的标准使用的方法。在目标2中，将建造高功率换能器，并将开发用于组织(体外)生物效应相关的暴露测量方法，用于一系列治疗方案，如纯热疗、机械治疗或联合治疗。在目标3中，我们使用一个健康的猪模型，研究了两个靶器官--肝脏和肾脏的肿瘤治疗。我们将使用代表现代临床系统的2D相控阵来实施一系列非线性HIFU协议。这些研究将解决肋骨和呼吸组织运动的干扰，允许在临床环境中仔细评估病变形成的精确度和控制。以前针对高功率临床治疗的工作没有涉及我们在这里提出的详细的基本特征。这项工作将通过提供准确评估HIFU暴露的工具，从而帮助制定监管指南，以促进FDA批准新的HIFU疗法，同时确定控制不善的系统，从而使公共卫生保健受益。这项工作还将推动HIFU走向更快、更安全的临床治疗。

DESCRIPTION (provided by applicant): High Intensity Focused Ultrasound (HIFU) is an emerging medical technology for thermally ablating targeted tissue within a mm-size focal 'hot spot' without damaging intervening tissues. In recent HIFU studies, there has also been significant interest in using purely mechanical destruction of tissue without thermal coagulation (histotripsy). Despite successful use of HIFU for the treatment of some benign and malignant tumors, broader clinical acceptance of this technology is impeded by incomplete regulatory standards for safety and efficacy. Current limitations include (a) a lack of established metrology standards to characterize HIFU fields; (b) an incomplete mechanistic understanding of thermal and mechanical bioeffects at high acoustic intensities, which hinders the quantification of dose given exposimetry information; and (c) clinical challenges such as long treatment times, acoustic obstacles like ribs, and the limited availability of cost-effective image guidance. This proposal addresses these limitations with a particular focus on treatments at high power levels. In the initial years of the grant, we explored HIFU treatments that utilize nonlinear acoustics and developed metrology tools for characterizing intense acoustic fields. We showed that shock formation leads to ultrasound absorption that is 10-100 times greater than for harmonic waves of the same intensity; consequently, boiling conditions at 100¿C can be reached within milliseconds. We developed a treatment method that uses sequences of millisecond-long, high-pressure pulses to deliver shocks waves at the focus. In such treatment regimes, tissue ablation is accelerated, the initiation of boiling facilitates image guidance with ultrasound, and tissue lesions can be controlled to exhibit mechanical damage, thermal damage, or both. The specific aims of this proposal build upon the previous work to advance nonlinear HIFU methods toward clinical adoption. In Aim 1, we will extend HIFU transducer characterization to complex array sources, and we will define methods suitable for standard use in performance assessment of clinical HIFU systems. In Aim 2, high power transducers will be built and the methods for correlating exposimetry with bioeffects in tissue (ex vivo) will be developed for a range of therapeutic regimes such as purely thermal, mechanical, or combined. In Aim 3, we examine tumor treatment in two target organs, the liver and the kidney, using a healthy porcine model. We will implement a range of nonlinear HIFU protocols using a 2D phased array representative of modern clinical systems. These studies will address interference from ribs and respiratory tissue motion, allowing careful assessment of the precision and control of lesion formation in a clinical setting. Previous work targeted at high-power clinical treatments has not involved the detailed fundamental characterizations that we propose here. The work will benefit public health care by providing tools for accurate evaluation of HIFU exposure, thereby aiding the development of regulatory guidelines to facilitate FDA approval of new HIFU therapies while identifying poorly controlled systems. The work will also advance HIFU toward faster and safer clinical treatments.